Most effective process for base-free preparation of ketone intermediates usable for manufacture of nebivolol

ABSTRACT

The invention relates to a process for the preparation of a ketone of a general formula 1 
     
       
         
         
             
             
         
       
     
     with X being Cl or Br, in particular with X being Cl, with Y being F, Cl, Br, I or H, in particular with Y being F,
 
comprising the steps of: activation of a carboxylic acid by using a peptide coupling agent, coupling of the activated carboxylic acid with a malonic acid derivative providing a β-ketoester precursor and converting the β-ketoester precursor to the ketone of the general formula 1.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional of co-pending U.S. patent application Ser. No.14/621,414, filed on Feb. 13, 2015, which in turn claims the benefit ofEuropean Patent Application No. 14155299.2, filed on Feb. 14, 2015. Thecontents of the foregoing patent applications are incorporated byreference herein in their entirety.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparationof a ketone needed for example as an intermediate for the synthesis ofNebivolol and its hydrochloride salt. The invention further relates tosaid ketones, the use of said ketones and methods applying said ketones.

BACKGROUND OF THE INVENTION

Nebivolol((±)-[(S,R,R,R)+(R,S,S,S)-]-α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzo-pyran-2-methanol])and its pharmaceutically active HCl salt—as disclosed in U.S. Pat. No.4,654,362 A and its counter EP 0145067 A2—is a potent and selective fluadrenergic blocker used for treatment of high blood pressure.Nebivolol*HCl (nebivolol hydrochloride) is applied as a racemate andconsists of the two enantiomers: d-nebivolol*HCl and l-nebivolol*HCl.

Numerous syntheses for the preparation of nebivolol hydrochloride havebeen disclosed, for example in U.S. Pat. No. 4,654,362 A (JANSSEN), EP0334429 A1 (JANSSEN), WO 2004/041805 A1 (EGIS), WO 2006/016376 A1 and WO2007/083318 A1 (HETERO DRUGS), WO 2006/025070 A2 (TORRENT), WO2008/010022 A2 (CIMEX), WO 2008/064826 A2 and WO 2008/064827 A2 (ZACH),WO 2009/082913 A1, CN 101463024 A, WO 2010/049455 (ZACH) and WO2010/089764 A1 (ZACH).

The challenge in each process for the manufacture of Nebivolol or itspharmaceutically active HCl salt is its unique structure as Nebivololcontains four chiral centers resulting in 16 theoretical isomers. Infact, the total number of diastereomers is reduced to only 10 due to thesymmetry plane through the N atom of the molecule. As a consequence,this symmetry plane provokes similar retrosynthetic cuts in most of thepublished syntheses.

Not surprisingly, most of the reported processes apply the reaction of6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran building blocks of theformula A (Scheme 1) of appropriate stereochemistry with formallyammonia, a suitably protected primary amine or azide ion.

Besides other methods, suitable precursors of epoxides of formula A arechloroalcohols B

reported for the first time in EP 1803715 A1. Usually, chloroalcoholscan be synthesized from chloroketones of formula C

which themselves can be prepared from chromane carboxylic acids, such as6-fluoro-chroman-2-yl-carboxylic acid, according to known techniques(see for example EP 1803715 A1, U.S. Pat. No. 7,650,575 B2).

In WO 2011/091968 A1 we disclosed a highly stereoselective approach forthe synthesis of racemic nebivolol (racemic mixture of d-nebivolol andl-nebivolol) as well as for the production of the individual enantiomersd-nebivolol and l-nebivolol based on enantiomerically pure chloroketonesand chloroalcohols.

The synthesis is performed according the general scheme 2.

For example, d-nebivolol Fa was prepared by enzymatic reduction of1-(2S)-(6-fluorochroman-2-yl)-2-chloroethan-1-one Ca and1-(2R)-(6-fluorochroman-2-yl)-2-chloroethan-1-one Cb to give either theS- or the R-configurated chloroalcohol Ba or Bb.(S)-2-chloro-1-((R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol Ba wassubjected to amination by treatment with sodium methoxide followed byreaction with benzylamine to give(S)-2-benzylamino-1-((R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanolDa. This underwent coupling with(R)-2-chloro-1-((R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol Bbfollowed by debenzylation to give d-nebivolol Fa. An analogue pathwayapplies if Bb was subjected to amination. l-Nebivolol Fb was produced ina similar way. Finally, d- and l-nebivolol (Fa and Fb) were mixed togive racemic nebivolol G which can be converted to the hydrochloridesalt.

Chloroketones C can be prepared from chromane carboxylic acids accordingto known techniques, e.g. WO 2008010022 A2 (Cimex) describes theconversion of 6-fluoro-chromanic acid to the corresponding acidchloride, followed by reaction with Meldrum's acid with the aid of abase. We found this process unsatisfactory when starting withenantiomerically pure 6-fluoro-chromanic acid since the base inducedpartial isomerisation.

Other known processes for the preparation of chloroketones (for exampleWO 2010/034927 A1) suffer from more general aspects as the processes arebased on organometallic chemistry. These processes need strong cryogenicconditions and are not feasible for industrial production from aneconomical point of view.

It is evident that partial isomerisation of the chloroketones C willresult in lower diastereomerical purity of chloroalcohols B which leadsto the formation of unwanted nebivolol diastereomers in the couplingstep. This has an impact not only on the yield but also on quality ofnebivolol.

The goal of the present invention is to provide a more suitable accessto enantiomerically pure chloroketones which can be used in themanufacture of nebivolol and, thus, providing an economic access toNebivolol in a high yield and high quality.

SUMMARY OF THE INVENTION

According to a first aspect, the invention relates to a process for thepreparation of a ketone of a general formula 1

-   -   with X being Cl or Br, in particular with X being Cl,    -   with Y being F, Cl, Br, I or H, in particular with Y being F.        comprising the steps of:

-   a. activation of a carboxylic acid of a general formula 2

-   -   by using a peptide coupling agent, with Y having the same        meaning as defined above,

-   b. coupling of the activated carboxylic acid with a malonic acid    derivative providing a β-ketoester precursor, in particular a    β-ketoester precursor of the general formula 6a or 6b,

-   -   with R⁴ being H or C₁ to C₆ alkyl, R⁵ being H or C₁ to C₆ alkyl,        R⁶ being H or C₁ to C₆ alkyl and R⁷ being C₁ to C₆ alkyl, or a        substituted or unsubstituted phenyl, in particular R⁶ being C₁        to C₃ alkyl and R⁷ being C₁ to C₃ alkyl,

-   c. converting the β-ketoester precursor to the ketone of the general    formula 1.

According to a second aspect, the invention relates to a preparation ofa chiral ketone of the general formula 1a or 1b,

with X and Y having the same meaning as defined previously, comprising apurity of ee>98%.

According to a third aspect, the invention relates to a preparation of achiral ketone of the general formula 1a or 1b, as defined above,producible by the process according to the first aspect of theinvention, comprising a purity of ee>98%.

According to a fourth aspect, the invention relates to a use of apreparation of a chiral ketone according to the second aspect of theinvention or a preparation of a chiral ketone according to the thirdaspect of the invention in the production of chiral alcohols of thegeneral formula 5a to 5d,

with X and Y having the same meaning as defined previously.

According to a fifth aspect, the invention relates to a use of thepreparation of a chiral ketone according to the second aspect of theinvention or a preparation of a chiral ketone produced according to thethird aspect of the invention in the production of d-nebivolol,l-Nebivolol or a mixture of d-nebivolol and l-Nebivolol, in particular aracemic mixture of d-nebivolol and l-Nebivolol, or the hydrochloridesalts thereof.

According to a sixth aspect, the invention relates to a process for thepreparation of an alcohol of a general formula 5a to 5d, as definedabove

comprising the steps of:

-   a. activation of a carboxylic acid of a general formula 2, in    particular of the formula 2a or 2b, by using a peptide coupling    agent, with formula 2, 2a or 2b having the same meaning as defined    above,-   b. coupling of the activated carboxylic acid with a malonic acid    derivative providing a β-ketoester precursor, in particular a    β-ketoester precursor of the general formula 6a or 6b, as defined    above,-   c. converting the β-ketoester precursor to the ketone of the general    formula 1, in particular of the ketone of formula 1a or 1b, as    defined above,-   d. reduction of the ketone of the general formula 1, in particular    reduction of the ketone of formula 1a or 1b, providing the alcohol    of the general formula 5a to 5d.

According to a seventh aspect, the invention relates to an alcohol of ageneral formula 5a to 5d, as defined above, comprising adiastereochemical purity >98%.

According to a eight aspect, the invention relates to an alcohol of ageneral formula 5a to 5d, as defined above, producible by the processaccording to the sixth aspect of the invention, comprising adiastereochemical purity >98%.

According to a ninth aspect, the invention relates to a use of thechiral alcohol according to the seventh aspect of the invention or apreparation of a chiral ketone produced according to the sixth aspect ofthe invention in the production of d-nebivolol, l-Nebivolol or a mixtureof d-nebivolol and l-Nebivolol, in particular a racemic mixture ofd-nebivolol and l-Nebivolol, or the hydrochloride salts thereof.

According to a tenth aspect, the invention relates to a process for thepreparation of d-nebivolol, l-Nebivolol or a mixture of d-nebivolol andl-Nebivolol, in particular a racemic mixture of d-nebivolol andl-Nebivolol, or the hydrochloride salts thereof

comprising the steps of:

-   a. activation of a carboxylic acid of a general formula 2, in    particular of the formula 2a or 2b, by using a peptide coupling    agent, with formula 2, 2a or 2b having the same meaning as defined    above,-   b. coupling of the activated carboxylic acid with a malonic acid    derivative providing a β-ketoester precursor, in particular a    β-ketoester precursor of the general formula 6a or 6b, as defined    above-   c. converting the β-ketoester precursor to the ketone of the general    formula 1, in particular of the ketone of formula 1a or 1b, as    defined above-   d. reduction of the ketone of the general formula 1, in particular    reduction of the ketone of formula 1a or 1b, providing a alcohol of    the general formula 5a to 5d, as defined above,-   e. provision of an protected aminoalcohol of the formula 7a to 7b,

-   -   with Y having the same meaning as defined previously and P being        an amine protecting group, derived form the alcohols of the        general formula 5a to 5d,

-   f. coupling of the aminoalcohol 7a with the alcohol 5b or the    aminoalcohol 7b with the alcohol 5a providing protected d-nebivolol,    or coupling of the aminoalcohol 7c with the alcohol 5d or the    aminoalcohol 7d with the alcohol 5c, providing protected    l-nebivolol,

-   g. deprotection, providing d-nebivolol or l-Nebivolol, wherein    optionally the d-nebivolol or l-nebivolol may be treated with    hydrochloric acid, wherein further optionally the d-nebivolol or    l-Nebivolol may be mixed providing a mixture of d-nebivolol or    l-nebivolol, in particular a racemic mixture, prior to the treatment    with hydrochloride acid.

As used herein the term “alkyl,” refers to a saturated straight orbranched hydrocarbon moiety containing up to 6, particularly up to 4carbon atoms. Examples of alkyl groups include, without limitation,methyl, ethyl, propyl, butyl, n-hexyl, iso-propyl, iso-butyl ortert-butyl and the like. Alkyl groups typically include from 1 to about6 carbon atoms (C₁ to C₆ alkyl).

As used herein the term “ee,” refers to an enantiomeric excess of asubstance. Enantiomeric excess is defined as the absolute differencebetween the enantiomers divided by the sum of the enatiomers and isexpressed in percent. An analogue definition applies for adiastereomeric excess (“de”), also referred to as “diastereochemicalpurity”.

A protecting group in the context of the present specification is agroup employed to reduce the reactivity of a particular moiety.Protecting groups are well known to the person skilled in the art oforganic chemistry. P. G. M. Wuts, “Greene's Protective Groups in OrganicSynthesis,” 4th ed. (2006, Wiley; ISBN 978-0-471-69754-1; 5th editionJune 2013 Wiley-Blackwell).

The term “substituted” refers to the addition of a substituent group toa parent compound.

“Substituent groups” can be protected or unprotected and can be added toone available site or to many available sites in a parent compound.Substituent groups may also be further substituted with othersubstituent groups and may be attached directly or by a linking groupsuch as an alkyl, an amide or hydrocarbyl group to a parent compound.“Substituent groups” amenable herein include, without limitation,halogen, oxygen, nitrogen, sulphur, hydroxyl, alkyl, alkenyl, alkynyl,acyl, carboxyl, aliphatic groups, alicyclic groups, alkoxy, substitutedoxy, aryl, aralkyl, heterocyclic radical, heteroaryl, heteroarylalkyl,nitro or cyano.

DETAILED DESCRIPTION OF THE INVENTION

It was evident from reactions in the racemic series (see example 1) thatthe preparation of chiral chloroketones via chiral acid chlorides andintermediate meldrumates is not suitable as this process resulted insubstantial racemisation, partially induced by ketene formation from theacid chloride under the influence of bases. Various bases (e.g.,pyridine, 2,6-lutidine, 2-chloropyridine, Na₃PO₄) and dosing regimeshave been investigated to overcome these problems, but the resultscouldn't be improved.

These intrinsic problems with acid chlorides could not be overcome byusing a formation of mixed anhydrides of 6-fluoro-chromanic acid andtheir conversion to chloroketones via known Meldrumate chemistry as itis illustrated below on the formation of the (S)-chloroketone(2-chloro-1-[(2S)-6-fluorochroman-2-yl]ethanone) from the chromanecarboxylic acid ((2S)-6-fluorochromane-2-carboxylic acid) (scheme 3).

Although ketene formation could be avoided completely when usingpivaloyl chloride for anhydride formation, however, now racemization ofthe enantiomerically pure chromanic acid anhydride occurred veryquickly, even if only a small excess of base is present in the reactionmixture. Interestingly, the meldrumate once it has been formed is stableagainst strong bases like diisopropylethylamine, even if the base isapplied in excess. Apparently, the reaction rate constant of (S)- or(R)-chromanic acid-anhydride formation is higher than the rate of itsconsumption by Meldrum's acid. Thus, the mixed anhydride accumulates andtherefore undergoes partial racemization during its short life timeunder reaction conditions. In general, chiral chloroketones couldn't beobtained with ee>94% by that approach (see example 2).

These results could also not be improved by optimising the base (e.g.exchanging diisopropylethylamine against 4-(Dimethylamino)-pyridin(DMAP), 4-picoline, 2-chloropyridine and others). DMAP failed to givethe mixed anhydride whereas 4-picoline and 2-chloro-pyridine were notsuperior regarding overall process yield and chiral purity. All attemptsto improve the results by optimising the stoichiometry also failed.Replacement of pivaloyl chloride by ethyl chloroformate was also noteffective.

Thus, all the known routes and variations thereof can not provideenantiomerically chloroketones in the necessary high purity. Allreaction conditions using different bases as catalysts were accompaniedby substantial racemisation at various steps of the overall processsequence.

The process according to the first aspect of the invention provides asolution to this problem. Surprisingly, the inventors found that peptidecoupling agents like 1-Hydroxybenzotriazol (HOBt), Oximapure andcarbonyldiimidazole (CDI) effected the conversion of FCA to themeldrumate without the need for a base.

A first aspect of the invention relates to a process for the preparationof a ketone of a general formula 1

-   -   with X being Cl or Br, in particular with X being Cl,    -   with Y being F, Cl, Br, I or H, in particular with Y being F.        comprising the steps of:

-   a. activation of a carboxylic acid of a general formula 2

-   -   by using a peptide coupling agent, with Y having the same        meaning as defined above,

-   b. coupling of the activated carboxylic acid with a malonic acid    derivative providing a β-ketoester precursor, in particular a    β-ketoester precursor of the general formula 6a or 6b,

-   -   with R⁴ being H or C₁ to C₆ alkyl, R⁵ being C₁ to C₆ alkyl, R⁶        being H or C₁ to C₆ alkyl and R⁷ being C₁ to C₆ alkyl or a        substituted or unsubstituted phenyl, in particular R⁶ being C₁        to C₃ alkyl and R⁷ being C₁ to C₃ alkyl

-   c. converting the β-ketoester precursor to the ketone of the general    formula 1.

The ketones of the general formula 1, in particular with X being Cl orBr and Y being F, are—either as a racemate or as enantiomerically purecompounds—useful intermediates in the preparation of nebivolol and itshydrochloride salt.

A general pathway is depicted in scheme 4 using the β-ketoesterprecursor of formula 6a as an example. Other β-ketoester precursor arealso possible.

As already discussed, there is a need to find a new method for providingketones of formula 1. Surprisingly, the inventors found that peptidecoupling agents allow a conversion of chromanic acid 2 to ketones 1 in avery high yield and purity. The use of peptide coupling agents allows aformation of the interim β-ketoester under neutral or even acidicconditions, thus, reducing the isomerisation substantially. Since thechemistry related to peptide coupling completely avoids the usage ofbases it provides a solution to the above mentioned problems withrespect to the substantial isomerisation occurring in the known routes.

In some embodiments, the malonic acid derivative of step b is

-   -   a malonic diester of the formula R⁴—O—C(═O)—CH₂—C(═O)—O—R⁵, with        R⁴ being a C₁ to C₆ alkyl and R⁵ being a C₁ to C₆ alkyl,    -   a malonic acid derivative of a formula 8

-   -   with R⁶ being C₁ to C₆ alkyl and R⁷ being C₁ to C₆ alkyl, in        particular R⁶ and R⁷ being C₁ to C₃ alkyl, more particularly R⁶        and R⁷ are C₁ alkyl (2,2-dimethyl-1,3-dioxane-4,6-dione;        Meldrum's acid) or    -   a malonic half ester of the formula R⁴—O—C(═O)—CH₂—C(═O)—O—H or        its Na- and Mg salts, with R⁴ being a C₁ to C₆ alkyl.

In some embodiments, the malonic acid derivative of step b is a malonicdiester of the formula R⁴—O—C(═O)—CH₂—C(═O)—O—R^(5′) with R⁴ being a C₁to C₆ alkyl and R⁵ being a C₁ to C₆ alkyl, providing the interimβ-ketoester of the formula 6a by a coupling reaction with the activatedcarboxylic acid of step a.

In some embodiments, the malonic acid derivative of step b is a malonicdiester the formula 8

with R⁶ being C₁ to C₆ alkyl and R⁷ being C₁ to C₆ alkyl, in particularthe malonic acid derivative is 2,2-dimethyl-1,3-dioxane-4,6-dione(Meldrum's acid), providing the interim β-ketoester of the formula 5b bya coupling reaction with the activated carboxylic acid of step a.

In some embodiments, the malonic acid derivative of step b is a malonichalf ester of the formula R⁴—O—C(═O)—CH₂—C(═O)—O—H or its Na- and Mgsalts, with R⁴ being a C₁ to C₆ alkyl, providing the interim β-ketoesterof the formula 6a by a coupling reaction with the activated carboxylicacid of step a.

In some embodiments, the activated carboxylic acid of step a is coupledwith 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrums acid) providing themeldrumate of a general formula 3

-   -   as the β-ketoester precursor.

In some embodiments, the peptide coupling agent is selected from thegroup of, triazoles, carbonylimidazoles or imminoacetates, particularthe peptide coupling agent is selected from the group ofcarbonylimidazoles.

In some embodiments, the peptide coupling agent is selected from thegroup of, 1-Hydroxybenzotriazol (HOBT), 1-Hydroxy-7-azabenzotriazol(HOAT), 1,1′-Carbonyldiimidazol (CDI),1,1′-carbonylbis(3-methylimidazoliumtriflate) (CBMIT) orEthylcyan(hydroxyimino)acetat (Oximapure®).

In some embodiments, the coupling of the activated carboxylic acid isachieved without the presence of a base additive.

The term “base additive” comprises a base according to the definition ofBrønsted and Lowry (“proton acceptor”), which is added before thecoupling step b of the carboxylic acid and the malonic acid derivativewith the exception of peptide coupling agents. Thus, the base additiveis present during the coupling reaction. The “base additive” may also beadded before the coupling step in a previous reaction step. A “baseadditive” according to the invention encompasses any bases which areadded to the reaction mixture for any reason, in particular for theactivation of the carboxylic acid derivative or in support of saidactivation (e.g. Diisopropylethylamine, pyridine, 2,6-lutidine,2-chloropyridine, Na₃PO₄). Bases (generally weak bases) which aregenerated during a reaction step (e.g. in the activation step with apeptide coupling agent) of the applied reagents (e.g. peptide couplingagents, malonic acid derivatives, carboxylic acids etc.) or as sidereactions of said reagents or the described reagents are not consideredas “bases additives” and, thus, not excluded during the reaction step.

It has to be noted that a peptide coupling agent, as specifiedpreviously, which might be defined according to the definition ofBrønsted and Lowry (“proton acceptor”), is not considered as a “baseadditive” according to the invention, and thus, not excluded.

In some embodiments, the coupling of the activated carboxylic acid isachieved in a reaction mixture comprising a pH in the range of 8 orless, in particular a pH in the range of 7 or less.

In some embodiments, the β-ketoester precursor of formula 6b, inparticular the meldrumate of the general formula 3, is converted to theketone of the general formula 1 by using a β-ketoester of the generalformula 4

as an intermediate, with Y having the same meaning as definedpreviously, wherein the compound of the general formula 4 is provided byalcoholysis of the β-ketoester precursor of the general formula 6b, inparticular the meldrumate of the general formula 3, with an alcoholR³OH, with R³ being C₁-C₆ alkyl.

In some embodiments, the compound of the general formula 4 ishalogenated, optionally hydrolyzed, and decarboxylized, to give theketone of the general formula 1.

A general reaction pathway using a β-ketoester of the general formula 4as an intermediate is depicted in Scheme 5.

In some embodiments, the β-ketoester precursor of formula 6a, in casethe β-ketoester precursor derived from a reaction with a malonic halfester of the formula R⁴—O—C(═O)—CH₂—C(═O)—O—H or its Na- and Mg salts,is decarboxylized to a β-ketoester of the general formula 4,subsequently halogenated and decarboxylized, to give the compound of thegeneral formula 1, with R⁴ having the same meaning as defined above.

In some embodiments, the chiral ketone of the general formula 1a or 1b

is provided by using the correspondent carboxylic acids of the generalformula 2a or 2b

with X and Y having the same meaning as defined previously.

The same process steps and the same reaction conditions discussed withrespect to the general formula 1 apply for providing a chiral ketone ofthe general formula 1a or 1b using the correspondent carboxylic acids ofthe general formula 2a or 2b.

It is understood that compounds depicted as a specific enantiomer ordiastereomer (eg. formula 1a, 1b, 2a, 2b, 5a, 5b, 5c or 5d) and referredto as “pure” comprises said enantiomer or said diastereomer in asubstantial excess, wherein the respective other possible enantiomers ordiastereomers may be present in a very small amount. If not statedotherwise, said compounds comprise the highest purity possible, in whichsaid compounds can be purchased, purified or synthesised.

The carboxylic acids of the general formula 2a or 2b is purchased in apurity of ee>99%.

In some embodiments, the preparation of the ketone of the generalformula 1, 1a or 1b is carried out as an one-pot-approach withoutisolation of any intermediate.

A second aspect of the invention relates to a chiral ketone of thegeneral formula 1a or 1b,

with X and Y having the same meaning as defined previously, comprising apurity of ee>98%.

A third aspect of the invention relates to a chiral ketone of thegeneral formula 1a or 1b, as defined above, producible by the processaccording to any one of the claims 1 to 11, comprising a purity ofee>98%.

The chiral ketones of the general formula 1a or 1b comprises a very highpurity (with respect to ee), which could not be obtained by the knownprocesses. In general, chiral chloroketones couldn't be obtained withee>94% (see example 2).

A fourth aspect of the invention relates to a use of a chiral ketoneaccording to the claim 12 in the production of chiral alcohols of thegeneral formula 5a to 5d,

with X and Y having the same meaning as defined previously.

The use of the ketones 1a and 1b in a purity of ee>98% leads, after areduction, in particular a stereospecific, enzymatic reduction, to thefour chiral pure alcohols 5a to 5d with a diastereochemical purity of>98%.

A fifth aspect of the invention relates to a use of the chiral ketoneaccording to the claim 12 in the production of d-nebivolol, l-Nebivololor a mixture of d-nebivolol and l-Nebivolol, in particular a racemicmixture of d-nebivolol and l-Nebivolol, or the hydrochloride saltsthereof.

The use of the ketones 1a and 1b as a starting material in a high purity(ee>98%) leads to the four chiral pure alcohols 5a to 5d in a highdiastereochemical purity of >98%, which are further precursors inproducing nebivolol. The use of starting materials and precursors insuch a high purity leads to less unwanted side products (which also maybe difficult to separate from the main product). Thus, providingd-nebivolol, l-Nebivolol, a mixture of d-nebivolol and l-Nebivolol orthe hydrochloride salts thereof in a high yield and very high purity.

A sixth aspect of the invention relates to a process for the preparationof an alcohol of a general formula 5a to 5d, as defined above

comprising the steps of:

-   a. activation of a carboxylic acid of a general formula 2, in    particular of the formula 2a or 2b, by using a peptide coupling    agent, with formula 2, 2a or 2b having the same meaning as defined    above,-   b. coupling of the activated carboxylic acid of formula 2 with a    malonic acid derivative, as defined above, providing a β-ketoester    precursor, in particular a β-ketoester precursor of the general    formula 6a or 6b, as defined above,-   c. converting the β-ketoester precursor to the ketone of the general    formula 1, in particular to the ketone of formula 1a or 1b, as    defined above,-   d. reduction of the ketone of the general formula 1, in particular    of the ketone of formula 1a or 1b, providing the alcohol of the    general formula 5a to 5d.

The reduction of the ketone of the general formula 1, in particular ofthe ketone of formula 1a or 1b, may be achieved by suitable standardreduction methods. The reduction of ketones to alcohols can beconsidered as basic knowledge of a person skilled in the art.

Particularly, a stereospecific, enzymatic reduction as disclosed in WO2011/091968 A1 (in particular section [00028] to [00030], [00034] to[00039]) is applied, leading to the four chiral pure chloroalcohols 5ato 5d with a diastereochemical purity of >98%.

A seventh aspect of the invention relates to an alcohol of a generalformula 5a to 5d, as defined above, comprising a diastereochemicalpurity of >98%.

An eight aspect of the invention relates to an alcohol of a generalformula 5a to 5d, as defined above, producible by the process accordingto the sixth aspect of the invention, comprising a diastereochemicalpurity >98%.

A ninth aspect of the invention relates to a use of the chiral alcoholaccording to claim 15 or a chiral alcohol according to the sixth aspectof the invention in the production of d-nebivolol, l-Nebivolol or amixture of d-nebivolol and l-Nebivolol, in particular a racemic mixtureof d-nebivolol and l-Nebivolol, or the hydrochloride salts thereof.

The use of the four chiral pure alcohols 5a to 5d in a highdiastereochemical purity of >98% as a precursor to Nebivolol providesless unwanted side products (which also may be difficult to separatefrom the main product). Thus, providing d-nebivolol, l-Nebivolol, amixture of d-nebivolol and l-Nebivolol or the hydrochloride salts in ahigh yield and very high purity.

A tenth aspect of the invention relates to a process for the preparationof d-nebivolol, l-Nebivolol or a mixture of d-nebivolol and l-Nebivolol,in particular a racemic mixture of d-nebivolol and l-Nebivolol, or thehydrochloride salts thereof

comprising the steps of:

-   a. activation of a carboxylic acid of a general formula 2, in    particular of the formula 2a or 2b, by using a peptide coupling    agent, with formula 2, 2a or 2b having the same meaning as defined    above,-   b. coupling of the activated carboxylic acid of formula 2 with a    malonic acid derivative, as defined above, providing a β-ketoester    precursor, in particular a β-ketoester precursor of the general    formula 6a or 6b, as defined above-   c. converting the β-ketoester precursor to the ketone of the general    formula 1, in particular to the ketone of formula 1a or 1b, as    defined above-   d. reduction of the ketone of the general formula 1, in particular    of the ketone of formula 1a or 1b, providing an alcohol of the    general formula 5a to 5d, as defined above,-   e. provision of an protected aminoalcohol of the formula 7a to 7b,

-   -   with Y having the same meaning as defined previously and P being        an amine protecting group, wherein the protected aminoalcohol of        the formula 7a to 7b is produced form the alcohols of the        general formula 5a to 5d,

-   f. coupling of the aminoalcohol 7a with the alcohol 5b or the    aminoalcohol 7b with the alcohol 5a providing protected d-nebivolol,    or coupling of the aminoalcohol 7c with the alcohol 5d or the    aminoalcohol 7d with the alcohol 5c, providing protected    l-nebivolol,

-   g. deprotection, providing d-nebivolol or l-Nebivolol, wherein    optionally the d-nebivolol or l-nebivolol may be treated with    hydrochloric acid, wherein further optionally the d-nebivolol or    l-Nebivolol may be mixed providing a mixture of d-nebivolol or    l-nebivolol, in particular a racemic mixture, prior to said    treatment with hydrochloride acid.

Concerning the steps d, e, f and g reference is made to the detaileddescription in the WO 2011/091968 A1 (in particular the examples 1 to 12on page 15 to 21). The same conditions and reagents are applied in theabove mentioned process of the tenth aspect of the invention.

Synthesis

The overall process for synthesis of pure ketones of formula 1a and 1band alcohols of formula 5a to 5d, derived from the ketones of formula 1aand 1b, is shown, without being limited to it, in one example (Scheme 6)

An analogue process applies for the use of chromanic acids of formula 2,2a or 2b with Y being Cl, Br, I or H. The same applies for bromoketonesof formula 1, 1a or 1b.

The activation of enantiomerically pure chromanic acids 2a′ and 2b′(ee>99%) by CDI and its conversion to the meldrumate proceeds under mildconditions at ambient temperature. Extensive HPLC and GC analysis showedthat there is no racemisation on this step. Meldrum's acid gives a cleanreaction with the activated chromanic acid to afford the meldrumatequantitatively. The following acidic ring-opening with subsequentesterification to the final β-ketoester also proceeded without problemsand didn't induce any racemisation (see EP 1803715 A1, in particular[0097] to [0110]). Conversion of the chiral ketoesters to chiralchloroketones 1a′ and 1b′ (and finally to chiral chloroalcohols 5a′ to5d′) by first chlorination using SO₂Cl₂ followed by acid induceddecarboxylation can be carried out as described in WO 2011/091968 A1, asdiscussed above concerning the reduction step, and EP 1803715 A1 section[0116] to [0119].

With the new process in hand it is possible to obtain (chloro)ketones ofthe formula 1a and 1b (respectively 1a′ and 1b′) with excellent purity(ee>98%). Overall yields of the conversion of chromanic acids to chiral(chloro)ketones are up to 80-85% which has to be considered as excellentfor the whole sequence. Thus, this approach is a very effective onedemonstrating its commercial and economical feasibility. Additionaladvantage can be taken from the fact that the synthesis of the(chloro)ketones can be carried out as one-pot process without isolationof all intermediates.

With the new optimised process in hand the final stereospecific,enzymatic reduction of (S)- and (R)-chloroketones leads to the fourchiral pure chloroalcohols using two different ADHs(alcoholdehydrogenase) with yields up to 99% and diastereochemicalpurity of >98%, respectively ee up to 99.8% (see scheme 7).

EXAMPLES Example 1: Ent-Chloroketone Via Acid Chloride and Meldrumate

78 g (2S)-6-Fluorochromanic acid 2a (e.e.>99%) is dissolved in toluene(300 ml) and reacted with thionyl chloride (52.3 g) at 65-70° C. untilcomplete conversion. The solvent is distilled off under vacuum. In aseparate flask dichloromethane (260 ml) is charged followed by pyridine(61 ml) and Meldrum's acid (62 g). After cooling to 0-5° C. thepreviously prepared acid chloride is added over 3 hrs at 0° C. Theresulting red brown slurry is stirred for additional 3 h min at 20-25°C. After complete conversion 1M HCl is added (121 g) and the phases areseparated. The organic phase is washed twice with 1M HCl (121 g) andfinally washed twice with water (120 ml). The remaining organic phase istransferred to another flask containing tert. butanol (56 g). Themixture is heated to 70-80° C. for 6 h under continuous distillation ofdichloromethane and acetone (CO2 evolvement) und normal pressure. Aftercooling to 55-60° C. tert. butanol is added again (53 g) and thereaction mixture heated again to 80° C. until no more distillate isobserved. The mixture is chilled to 20-25° C. and 1M HCl (140 g) isadded. The phases are separated and the organic phase is washed twicewith sat. NaHCO₃ solution (148 g). The organic phase is concentratedunder vacuum. The crude reaction product is transferred to a furtherflask and dissolved in ethyl acetate (500 ml). Na₃PO₄ (66 g) is addedand the mixture cooled to 10-15° C. Sulfuryl chloride (61 g) is addedslowly by keeping the temperature below 20° C. After complete conversionthe mixture is treated with water (175 ml). The phases are separated andthe organic phase treated again with water (70 ml). After phaseseparation the organic phase is concentrated in vacuum. The crudeproduct is dissolved in ethyl acetate (40 ml) and mixed at ambienttemperature with glacial acetic acid (291 ml) followed by 37% HCl (52ml). The reaction mixture is heated to 40° C. for 3 h. After cooling to20-25° C. toluene (140 ml) and water (100 ml) is added. The organicphase is washed twice with water (70 ml) and sat. NaHCO₃ solution (70ml). After additional washing with water (70 ml) the organic phase isconcentrated in vacuo. The resulting crude product is treated withisopropanol (165 ml) at 20-25° C. The mixture is stirred 2 h at 0-5° C.The product is filtered off and dried to give 1a′ (36 g; e.e. 93.5%) asyellow crystals.

In an analogous manner (2R)-6-fluorochromanic acid 2b can be convertedto chloroketone 1b′.

Example 2: Chloroketone Preparation with PivCl and Huenig Base

(2S)-6-fluorochromanic acid (11.59 kg) 2a, Meldrum's acid (9.4 kg) andDMAP (0.6 kg) are dissolved in acetonitrile (33.7 1) at 20-25° C.N-ethyl diisopropylamine (16.7 kg) is added during 20 min at 20-25° C.Pivaloyl chloride (8.0 kg) is added to the clear yellow solution over 2h. The solution is diluted with acetonitrile (6.2 1) and stirred foradditional 4-5 h at 45-50° C. Tert. butanol (16.1 kg) is added, followedby trifluoroacetic acid (10.2 kg). The mixture is heated to 50-55° C.and stirred for additional 7 h. Solvents are distilled off under vacuumand the residue is dissolved in toluene (31.4 kg) after cooling to20-25° C. Water (23 1) is added and the phases are separated. Theorganic phase is washed with sat. NaHCO₃ solution (23 1). The organicphase is washed again with water (23 1) and finally the solvents aredistilled off to give the crude β-ketoester (19.0 kg). The product istransferred to a second vessel and dissolved in ethyl acetate (70.2 kg).Na₃PO₄ (9.7 kg) is added and the mixture cooled to 10° C. Sulfurylchloride (9.0 kg) is dropped to the mixture during 2 h at 10° C. Aftercomplete conversion excess of sulfuryl chloride is hydrolysed with water(25.5 kg). The water phase is split off and discharged. The organicphase is washed with water (10.4 kg) and subsequently concentrated undervacuum to give 36.1 kg crude chlorinated β-ketoester. The crude materialis treated with glacial acetic acid (42.8 kg) and 37% HCl (9.1 kg) at20-25° C. and thereafter heated to 30-40° C. for about 7 h. Aftercooling to 20-25° C. toluene (17.8 kg) and water (20.4 kg) is added.After stirring for 30 min the phases are separated. The water phase isdischarged and the organic phase washed twice with water (10.4 kg), sat.NaHCO₃ solution (11.0 kg) and finally with water (10.4 kg). The solventsare distilled off to yield a yellow-orange-oil. Isopropanol (38.0 kg) isadded and half of the solvent is distilled off. The mixture is cooled to0-5° C. and stirred 3 h. The precipitate is filtered off to give 6.86 kg1a (50% of theoretical yield) of 95.8% purity (HPLC) and e.e. 96.2%(determined by chiral GC).

In a similar manner (2R)-6-fluorochromanic acid 2b (10.3 kg) isconverted to 1b (6.1 kg) in 50.7% yield. Purity as determined by HPLC is96.8% with e.e 93.2% (chiral GC).

Example 3: CDI-Process

CDI (100.7 kg) were charged in a vessel and suspended with acetonitrile(192 kg). A solution of (2R) 6-fluorochromanic acid 2a (110.7 kg) inacetonitrile (150 kg) was added over 45 min at 15-20° C. and stirred foradditional 60 min until conversion has completed. A solution ofMeldrum's acid (93.6 kg) in acetonitrile (97 kg) was added to themixture at 15° C. After stirring for 12 h tert. butanol (169.5 kg) wasadded. The resulting mixture was cooled to 0-5° C. Trifluoroacetic acid(168 kg) was dropped to the mixture at 5° C. over 2 h and stirred for6-7 h at 15-20° C. After complete conversion of the Meldrumate thesolvent was removed by distillation. The resulting oily residue wasdissolved in of toluene (279 kg) and washed with water (203 1), thentwice with saturated aqueous NaHCO₃-solution (67 kg) and again withwater (185 1). After phase separation, the aqueous layers were discardedand the toluene phase distilled off to give a slightly yellow oil whichwas azeotropically dried with toluene. The oily residue of(R)-FCA-β-ketoester in the reactor was dissolved in ethyl acetate (742kg). Na₃PO₄ (92.5 kg) was added and the suspension transferred to afurther vessel. Sulfurylchloride (87.6 kg) was added slowly at 0-5° C.over a period of 2 hours. The mixture was heated to 20° C. and stirreduntil completion of the reaction. Water (284 1) was added under stirringkeeping the temperature below 15° C. After phase separation, the loweraqueous layer was discarded and the upper organic layer was washed water(138 1). The solvent was stripped under reduced pressure to give the(R)-FCA-α-chloro-β-ketoester as a yellow oily residue which wasdissolved in glacial acetic acid (389.8 kg). Subsequently, 37% HCl (83.4kg) was added and the mixture heated to 40° C. for 4 h. The mixture wascooled to 10° C. and 204 kg of sat. NaCl solution (204 kg) and toluene(162 kg) were added. After phase separation the organic phase was washedtwice with brine (108 kg). The combined aqueous phases were re-extractedonce with toluene (45 kg). Under vigorous stirring, saturatedNaHCO₃-solution (65 1) was carefully added to the combined organicphase. After phase separation, the lower aqueous layer was discarded andthe upper organic layer was washed twice with an aqueous solution ofNa₂SO₄. Phases were separated and the organic phase concentrated underreduced pressure to yield an oily residue. Isopropanol (131 kg) wasadded and the residue dissolved at 40° C. A precipitate was obtained bycooling to 0° C. After additional stirring for 2 h the precipitate wasfiltered off. The filter cake was washed three times with ice-coldisopropanol and subsequently dried under reduced pressure. The motherliquor was reduced to the third part and crystallization was inducedagain by cooling to 0° C. The crystals were filtered off and both cropscombined to yield 1b (92.45 kg; 71.6% of theoretical yield). Purity was99% as determined by HPLC with e.e. 97.9% as determined by chiral GC.

Manufacturing of the corresponding (S)-chloroketone 1a was performed inthe same manner.

Example 4: Conversion to Chloroalcohols (5a to 5d) Preparation of theBuffer Solution for the Enzymatic Reduction:

Dissolve triethanolamine (4 g; 26.5 mmol) in water (215 ml). Adjust thepH of the solution, while stirring, to pH6.99 using 36% HCl (2.3 g). AddZnCl₂ (0.057 g) and fill up to 270 ml.

Then add glycerol (37.5 g) and mix well.

General Procedure for the Enzymatic Reduction:

Place isopropanol (20 g) in a flask and chill with ice to 0-5° C. Addβ-NAD (10 mg) and then add pre-chilled buffer solution (10 ml).Subsequently, add 50 mmol of the chloroketone at 0° C. to the reactionmixture and finally add 6,000 units (S)- or (R)-selective alcoholdehydrogenase. Warm up the sample to 20-25° C. and stir for 24 h. Afterconversion is complete, centrifuge the reaction solution and extractwith ethyl acetate (2×10 ml) after separating the phases. Wash theorganic phases with sat. NaCl solution (20 ml) and then dry over Na₂SO₄.The raw product is obtained through removal of the solvent bydistillation in vacuum.

(S)-2-chloro-1-((R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanol 5b′:

(2S)-6-Fluorochroman-2-yl-2-chloroethan-1-one 1a′ and (R)-selectivealcohol dehydrogenase were used in accordance with the specificationsprovided above to obtain 11.42 g (99% theoretical yield) 5b′ (d.e.98.3%; e.e. 99.8%).

LC-MS: m/z=230.232 (MH+, 100%)

(R)-2-chloro-1-((R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanol 5d′:

In analogous manner (2R)-6-Fluorochroman-2-yl-2-chloroethan-1-one 1b′and (R)-selective alcohol dehydrogenase were used to obtain 11.07 g (96%of theoretical yield) 5d′ (d.e. 97.9%; e.e. 99.8%)

LC-MS: m/z=230.232 (MH+, 100%)

(R)-2-chloro-1-((S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanol 5c′:

In analogous manner (2R)-6-Fluorochroman-2-yl-2-chloroethan-1-one 1b′and (S)-selective alcohol dehydrogenase were used to obtain 11.42 g (99%of theoretical yield) 5c′ (d.e. 98.0%; e.e. 99.8%)

LC-MS: m/z=230.232 (MH+, 100%)

(S)-2-chloro-1-((S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanol 5a′:

In analogous manner (2S)-6-Fluorochroman-2-yl-2-chloroethan-1-one 1a′and (S)-selective alcohol dehydrogenase were used to obtain 10.72 g (93%of theoretical yield) 5a′ (d.e. 98.1%; e.e. 99.9%)

LC-MS: m/z=230.232 (MH+, 100%)

In view of the many possible embodiments to which the principles of thedisclosed invention may be applied, it should be recognized that theillustrated embodiments are only preferred examples of the invention andshould not be taken as limiting the scope of the invention. Rather, thescope of the invention is defined by the following claims. We thereforeclaim as our invention all that comes within the scope and spirit ofthese claims.

We claim:
 1. A process for the preparation of a ketone of a generalformula 1

with X being Cl or Br, in particular with X being Cl, comprising thesteps of: a. reacting a carboxylic acid of a general formula 2

with a peptide coupling agent to yield an activated carboxylic acid, b.reacting the activated carboxylic acid with a malonic acid derivative,yielding a β-ketoester precursor, in particular a β-ketoester precursorof the general formula 6a or 6b,

c. converting the β-ketoester precursor to the ketone of the generalformula 1, wherein R⁴ and R⁶ independently of one another are H or C₁ toC₆ alkyl, R⁵ is C₁ to C₆ alkyl, R⁷ is C₁ to C₆ alkyl or a substituted orunsubstituted phenyl, in particular R⁶ is C₁ to C₃ alkyl and R⁷ is C₁ toC₃ alkyl, and Y is F, Cl, Br, I or H, in particular F.
 2. The processaccording to claim 1, wherein the malonic acid derivative is a malonicdiester of the formula R⁴—O—C(═O)—CH₂—C(═O)—O—R⁵, or a malonic acidderivative of a formula 8

or a malonic half ester of the formula R⁴—O—C(═O)—CH₂—C(═O)—O—H or itsNa- and Mg salts, with R⁴ being a C₁ to C₆ alkyl, wherein R⁴ is a C₁ toC₆ alkyl and R⁵ is a C₁ to C₆ alkyl, R⁶ is C₁ to C₆ alkyl and R⁷ is C₁to C₆ alkyl or a substituted or unsubstituted phenyl, in particular R⁶and R⁷ is C₁ to C₃ alkyl, more particularly R⁶ and R⁷ are C₁ alkyl. 3.The process according to claim 1, wherein the activated carboxylic acidof step a is coupled with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum'sacid) providing the meldrumate of a general formula 3

as the β-ketoester precursor.
 4. The process according to claim 1,wherein the peptide coupling agent is selected from the group oftriazoles, carbonylimidazoles or imminoacetates, in particularcarbonylimidazoles.
 5. The process according to claim 4, wherein thepeptide coupling agent is selected from the group of1-hydroxybenzotriazol (HOBT), 1-hydroxy-7-azabenzotriazol (HOAT),1,1′-carbonyldiimidazol (CDI),1,1′-carbonylbis(3-methylimidazoliumtriflate) (CBMIT) orethylcyan(hydroxyl-imino)acetat (Oximapure).
 6. The process according toclaim 1, wherein no base additive is present in step b (reacting theactivated carboxylic acid).
 7. The process according to claim 1, whereinthe step a is conducted in a reaction mixture comprising a pH in therange of 8 or less, in particular a pH in the range of 7 or less.
 8. Theprocess according to claim 1, wherein a β-ketoester of the generalformula 4

is an intermediate, in particular provided by alcoholysis of theft-ketoester precursor of the general formula 6b, in particular byalcoholysis of the meldrumate of the general formula 3, with an alcoholR³OH, with R³ being C₁-C₆ alkyl.
 9. The process according to claim 8,wherein the compound of the general formula 4 is halogenated, optionallyhydrolyzed, and decarboxylized, to give the ketone of the generalformula
 1. 10. The process according to claim 1, wherein the β-ketoesterprecursor of formula 6a, in case the β-ketoester precursor derived froma reaction with a malonic half ester of the formulaR⁴—O—C(═O)—CH₂—C(═O)—O—H or its Na- and Mg salts, is decarboxylized to aβ-ketoester of the general formula 4, subsequently halogenated anddecarboxylized, to give the ketone of the general formula 1, with R⁴having the same meaning as defined above.
 11. The process accordingclaim 1, wherein the chiral ketone of the general formula 1a or 1b

is provided by using the correspondent carboxylic acids of the generalformula 2a or 2b

with X and Y having the same meaning as defined previously.
 12. Apreparation of a chiral ketone of the general formula 1a or 1b

with X and Y having the same meaning as defined previously, having apurity of ee>98%, in particular a preparation of a chiral ketone of thegeneral formula 1a or 1b producible by the process according to any oneof the claims 1 to 11, having a purity of ee>98%.
 13. Use of thepreparation of a chiral ketone according to claim 12, or of thepreparation of a chiral ketone of the general formula 1a or 1b producedby the process according to claim 1, in the production of chiralalcohols of the general formula 5a to 5d,

wherein X and Y have the same meaning as defined previously.
 14. Use ofthe preparation of a chiral ketone of the general formula 1a or 1baccording to claim 12 or of the preparation of a chiral ketone of thegeneral formula 1a or 1b produced by the process according to claim 1 inthe production of d-nebivolol, l-nebivolol or a mixture of d-nebivololand l-nebivolol, in particular a racemic mixture of d-nebivolol andl-nebivolol, or the hydrochloride salts thereof.
 15. A preparation of achiral alcohol of the general formula 5a to 5d

having a diastereochemical purity >98%.